Several arene and alkene oxides are known to react covalently with macromolecules, including nucleic acids, and to transform cells in vitro, suggesting their role as ultimate carcinogens, mutagens, and cytotoxins. We are studying the cytochrome P-450-dependent monooxygenases, which convert unsaturated hydrocarbons to epoxides, and the further metabolism of arene and alkene oxides by soluble fraction glutathione transferases and microsomal epoxide hydrolase in hepatic and extrahepatic tissues. Experiments are conducted at various levels of cellular organization (isolated cells, perfused organs, purified enzymes) in an attempt to understand the mechanisms of organ-specific and cell-specific toxicity mediated by compounds metabolized to epoxides. Particular attention is being given to the respiratory tract because this is a common site for pollutant-mediated damage. Current research objectives are: 1) to characterize, both stereochemically and kinetically, the biotransformation of several K-region polycyclic arene oxides by purified glutathione transferases of mammalian and marine vertebrate origin; 2) to develop cell selective and isozyme specific suicide inhibitions of rabbit pulmonary cytochrome P-450 for use in studying relationships between chemical metabolism and target cell toxicity in lung; 3) to ascertain the chemical mechanisms by which alkylbenzenes selectively destroy rabbit pulmonary cytochrome P-450; 4) to determine the role of the vasculature in cytochrome P-450-mediated metabolism; 5) to biochemically characterize marine and mammalian NADPH-cytochrome P-450 reductases that exhibit differences in thermal lability and/or redox state; and 6) to determine relationships between total (polar and nonpolar benzo(a)pyrene metabolite profiles and BP-metabolite-DNA adduct profiles in perfused lungs and cells isolated from the lungs or trachea (both freshly isolated and cultured cells).